Angelica sinensis extract promotes neuronal survival by enhancing p38 MAPK-mediated hippocampal neurogenesis and dendritic growth in the chronic phase of transient global cerebral ischemia in rats
Angelica sinensis extract promotes neuronal survival by enhancing p38 MAPK-mediated hippocampal neurogenesis and dendritic growth in the chronic phase of transient global cerebral ischemia in rats
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DOI：
10.1016/j.jep.2021.114301
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发表时间：
2021-06-08
影响因子：
5.4
通讯作者：
Lee, Yu-Chen
中科院分区：
文献类型：
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作者：
Cheng, Chin-Yi;Huang, Hui-Chi;Lee, Yu-Chen
民族药理学相关性：当归（Oliv.）Diels（ASD），俗称当归，是一种流行的中药，长期以来一直用于治疗缺血性中风。然而，ASD在慢性脑缺血中的作用及其机制尚不清楚。研究目的：本研究旨在确定ASD提取物对短暂性全脑缺血（GCI）后28 d海马神经元存活的影响，并探讨p38丝裂原活化蛋白激酶（MAPK）相关信号通路参与海马神经发生的确切机制。材料和方法：大鼠行四血管闭塞25分钟。ASD提取物以0.25 g/kg的剂量灌胃给药（ASD-0.25 g），0.5 g/kg（ASD-0.5 g）、1 g/kg（ASD-1 g）、二甲亚砜给药后1 g/kg（D + ASD-1 g），或在短暂GCI后1、3、7、10、14、17、21和24 d给予SB 203580（p38 MAPK抑制剂）后1 g/kg（SB + ASD-1 g）。结果如下：ASD-0.5 g、ASD-1 g和D + ASD-1 g处理具有以下作用：上调海马齿状回（DG）中溴脱氧尿苷（BrdU）和Ki 67的表达，以及BrdU/神经元核（NeuN）和Ki 67/nestin的共表达;微管相关蛋白2/NeuN共表达以及NeuN和胶质细胞酸性蛋白（GFAP）表达的上调，下调海马CA1区肿瘤坏死因子-α/GFAP共表达;磷酸化p38 MAPK的上调（p-p38 MAPK），磷酸cAMP反应元件结合蛋白（p-CREB），脑源性神经营养因子（BDNF），胶质细胞系源性神经营养因子（GDNF），和海马中血管内皮生长因子A（VEGF-A）的表达。SB + ASD-1g处理可消除ASD-1g对这些蛋白表达的影响。结论：ASD-0.5 g和ASD-1 g治疗通过增强海马神经发生促进神经元存活。ASD提取物对星形胶质细胞相关的海马神经发生和树突生长的影响是由短暂GCI后28 d海马中p38 MAPK介导的CREB/BDNF、GDNF和VEGF-A信号通路的激活引起的。
Ethnopharmacological relevance: Angelica sinensis (Oliv.) Diels (ASD), commonly known as Dang Gui, is a popular Chinese herb that has long been used to treat ischemic stroke. However, the effects of ASD in chronic cerebral ischemia and its underlying mechanisms still remain unclear. Aim of the study: This study aimed to determine the effects of the ASD extract on hippocampal neuronal survival at 28 d after transient global cerebral ischemia (GCI) and to investigate the precise mechanisms underlying the p38 mitogen-activated protein kinase (MAPK)-related signaling pathway's involvement in hippocampal neurogenesis. Materials and methods: Rats underwent 25 min of four-vessel occlusion. The ASD extract was intragastrically administered at doses of 0.25 g/kg (ASD-0.25 g), 0.5 g/kg (ASD-0.5 g), 1 g/kg (ASD-1 g), 1 g/kg after dimethyl sulfoxide administration (D + ASD-1 g), or 1 g/kg after SB203580 (a p38 MAPK inhibitor) administration (SB + ASD-1 g) at 1, 3, 7, 10, 14, 17, 21, and 24 d after transient GCI. Results: ASD-0.5 g, ASD-1 g, and D + ASD-1 g treatments had the following effects: upregulation of bromodeoxyuridine (BrdU) and Ki67 expression, and BrdU/neuronal nuclei (NeuN) and Ki67/nestin co-expression in the hippocampal dentate gyrus (DG); upregulation of microtubule-associated protein 2/NeuN co-expression, and NeuN and glial fibrillary acidic protein (GFAP) expression, and downregulation of tumor necrosis factor-alpha/GFAP co-expression in the hippocampal CA1 region; upregulation of phospho-p38 MAPK (p-p38 MAPK), phosphocAMP response element-binding protein (p-CREB), brain-derived neurotrophic factor (BDNF), glial cell linederived neurotrophic factor (GDNF), and vascular endothelial growth factor A (VEGF-A) expression in the hippocampus. SB + ASD-1 g treatment abrogated the effects of ASD-1 g on the expression of these proteins. Conclusions: ASD-0.5 g and ASD-1 g treatments promotes neuronal survival by enhancing hippocampal neurogenesis. The effects of the ASD extract on astrocyte-associated hippocampal neurogenesis and dendritic growth are caused by the activation of p38 MAPK-mediated CREB/BDNF, GDNF, and VEGF-A signaling pathways in the hippocampus at 28 d after transient GCI.